Hyperandrogenemic disorders, such as polycystic ovarian syndrome (PCOS) affect 7-8% of women and are a leading cause of female infertility. PCOS is a complex heterogeneous disorder, characterized by excess activation of the reproductive neuroendocrine axis, hyperandrogenemia, and irregular or absent menstrual cycles and metabolic consequences. Although the causes of PCOS are not known and may in fact be multiple, both clinical observations and substantial animal work suggest one possible etiology for this disorder is prenatal exposure to androgens. In mice, in utero exposure to the non-aromatizable androgen dihydrotestosterone (DHT) generates female offspring that exhibit androgen excess, increased excitatory neurotransmission to gonadotropin-releasing hormone (GnRH) neurons, increased GnRH neuronal activity resulting in increased luteinizing hormone (LH) release, and metabolic disruptions. Together these lead to altered estrous cyclicity and reproductive dysfunction. Although animal models cannot completely replicate any human disorder, these prenatally androgenized (PNA) mice serve as a basic model for investigating mechanisms of the disorder and novel therapeutic targets. The proposed experiments are based on the working hypothesis that development of reproductive and metabolic disorders in PCOS is the result of multiple stimulatory interactions among these systems, and that interrupting these interactions at various points may reset the overall system leading to restoration of normal endocrine function. Specific aims 1 and 2 will test novel central and peripheral strategies for intervention. Specific aim 1 will test the hypothesis that a metabotropic glutamate receptor agonist will reduce the elevated GABAergic transmission to GnRH neurons in PNA mice, thereby decreasing GnRH neuronal activity and normalizing reproduction. Specific aim 2 will test the hypothesis that galardin, a matrix metalloproteinase inhibitor, will reduce steroidogenesis and/or normalize ovarian matrix resulting in restored estrous cyclicity, hormone profiles, glucose tolerance and fertility. Further, both aims will investigate if early (i.e., prepubertal) intervention can ameliorate the PNA phenotype in adulthood. Treated and untreated control and PNA mice will be evaluated for hormone levels, altered external genitalia, pubertal onset, altered estrous cyclicity, fertility, and glucose tolerance. PUBLIC HEALTH RELEVANCE: The proposed research plan will not only improve overall understanding of the basic pathophysiology of the development of PCOS, but will also allow investigation of novel targets for intervention. If these interventions are successful, it may broaden our now limited treatment for this common disorder.